Studies On The Tandem Reactions Of Stable Sulfur Ylides And Electron-Deficient Components

In this dissertation, we have highlighted recent advances on the chemistry of sulfur ylides and then described our works in this field. At first, we have disclosed the discovery of an unexpected tandem reaction and the rational design of novel cascade reactions on the basis of the mechanism investigation. Furthermore, we have developed two efficient strategies to achieve the asymmetric reactions of sulfur ylides and electron-deficient components. The key discoveries are listed below.1. An unprecedented reaction between sulfur ylides and nitroolefins has been disclosed to afford diverse and structurally complex oxazolidin-2-ones in 15-95% yields and≥95:5 dr. Significantly, many other useful synthetic building blocks such as vicinal amino diols and a-hydroxyl-β-amino acids are easily accessed from these oxazolidin-2-ones. More importantly, based on a series of experiments such as isotope-labeling experiments (D and 13C), intermediate capture and reaction tracking with NMR, we proposed a possible mechanism to account for this new reaction. The reaction was supposed to pass through mechanism-discriminative processes catalyzed by Br(?)nsted acid and base in sequence:Brensted acid-catalyzed formal [4+1] cycloadditions between sulfur ylides and nitroolefins, and Br(?)nsted base-catalyzed rearrangements of the corresponding cyclic nitronate intermediates.2. In the course of the mechanism investigation on the above-mentioned unprecedented transformation, we found the existence of a transiently generated cyclic nitronate. In principle, this cyclic nitronate is a 1,3-dipole which can react with electron-deficient components in situ. Accordingly, we proposed a novel reagent, alkene-tethered nitroolefins, and successfully developed the first inter-[4+1]/intra-[3+2] cycloaddition cascade of sulfur ylides. This novel and catalyst-free strategy allows rapid access to fused heterocyclic architectures in highly chemo-and diasteroselectivity (75-99% yields,≥95:5 dr), which could be further transformed to chromans bearing an attractive pyrroline ring and many other function groups such as amino, hydroxyl and ester. Note that only one manipulation in this tandem reaction could construct three new rings, four new chemical bonds and five consecutive stereocenters.3. By tuning the electronic effect ofα,β-unsaturated imines to stabilize the key zwitterionic intermediates generated from the Michael addition, we first accomplish the formal [4+1] cylcoaddition of sulfur ylides and unsaturated imines in high chemoselectivity. By means of the atropisomeric sulfide derived from S-or R-BINOL as the stereocontroller, the asymmetric version of this novel [4+1] annulation was performed to generate enantiomerically enriched structure-diverse pyrroline-2-carboxylates in high yields (83-99%) and excellent stereoselectivities (up to 98% ee, >95:5 dr.). Notably, these products could be readily converted into other useful functional molecules. More importantly, we established the configuration of chiral ylides in solution by X-ray analysis and 2D NMR spectroscopy, and then proposed a cisoid/quasi-[4+2] addition model to rationalize the stereoinduction of the asymmetric [4+1] annulation.4. Inspired by the success of an atropisomeric inducement strategy in the [4+1] pyrroline annulations, we continued to apply this strategy to the enantioselective tandem reactions between sulfur ylides and nitroolefins. Under the optimum reaction conditions, yields and stereoselectivities of chiral oxazolidinones are among the moderate to good level (15-71% yields, up to 96% ee and>95:5 dr). In addition, the asymmetric [4+1]/[3+2] cycloaddition cascade of sulfur ylides was also investigated with moderate results (54-95% yields, up to 75% ee and 95:5 dr). More importantly, we have studied the asymmetric course of these tandem reactions by DFT calculation. It was found that the intramolecular O-alkylation in the [4+1] annulation is the rate-and stereo-determined step. Furthermore, the first Michael addition in the cascade reaction was found to be a reversible process.5. In order to further improve the reaction efficiency, we have established an alternative method: catalytic asymmetric reaction of sulfur ylides with electron-deficient components. By rationally screening a series of H-bonding catalysts in details, a C2 symmetric chiral urea was found to be the best choice for the asymmetric [4+1]/[3+2] cascade cycloaddition. Under the optimal reaction conditions, the optically active fused heterocycles was delivered in good to excellent yields (63-99% yields) with greatly improved stereoselectivies (up to 80% ee and 95:5 dr). Remarkably, we have also investigated the stereocontrol course of the asymmetric [4+1]/[3+2] cycloaddition cascade and established a model of Lewis acid/base cooperative catalysis in virtue of non-linear effect experiment, in situ IR experiment, Job method, H-bonding titration and DFT calculation.6. We have significantly extended the success of H-bonding catalysis to asymmetric synthesis of chiral oxazolidinones. This reaction affords the desired products in moderate to excellent yields (65-96% yields) and good to excellent stereoselectivies (up to 94% ee and 95:5 dr). It was found that the good enantioselectivity was attributed to the stronger H-bonding strength between nitroolefins and H-bonding catalysts (compared with the above-mentioned [4+1]/[3+2] cascade reaction). Note that formidable alkyl- and alkenyl-substituted nitroolefins or sulfur ylides were well tolerated in this reaction (65-87% yields, up to 94% ee and 95:5 dr). Perhaps more significantly, we also successfully applied this methodology to the total synthesis of (+)-epi-Cytoxazone and (-)-Valinotin A with reduced synthetic steps compared with previous reports.